Legionnaires' disease is a highly fatal pneumonia that occurs worldwide in both epidemic and endemic form. An estimated 100,000 cases occur annually in the United States. It is an important cause of fatal nosocomial pneumonia, and it plagues major transplant centers. The causative agent, Legionella pneumophila, is an intracellular bacterial pathogen. Previous studies from this laboratory have extensively explored the interaction of L. pneumophila with human mononuclear phagocytes and defined immune responses to this pathogen. These studies have indicated that cell-mediated immunity plays a dominant role in host defense against this organism. Investigations conducted during the first 2 years of this project have identified 3 L. pneumophila vaccines effective against L. pneumophila infection in an animal mode. These investigations have laid the foundation for further studies aimed at identifying molecules and epitopes of these molecules important to cell-mediated and protective immunity against L. pneumophila. Such studies hold great promise for the development of an effective vaccine against Legionnaires' disease. Specific aims of this proposal are to: A. Determine optimal conditions for induction of protective immunity by L. pneumophila vaccines; B. Determine if immunization with L. pneumophila vaccines induces long- lasting immunity in guinea pigs; C. Determine if immunization with vaccines derived from L. pneumophila serogroup I induces protective immunity to other serogroups of L. pneumophila and other species in the Family Legionellaceae; D. Identify key epitopes of antigens that induce protective immunity; E. Identify additional L. pneumophila components and products to which immune guinea pigs have developed a cell-mediated and humoral immune response; F. Determine the capacity of additional L. pneumophila components or products to induce specific cell-mediated and humoral immune responses in guinea pigs; G. Determine if immunization with additional L. pneumophila components and products that induce cell- mediated immunity establishes protective immunity against L. pneumophila in guinea pigs; H. Determine the capacity of specific L. pneumophila components or products to stimulate human cell-mediated immunity.